CN108047128A - 一种合成(e)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法 - Google Patents

一种合成(e)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法 Download PDF

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CN108047128A
CN108047128A CN201711398046.3A CN201711398046A CN108047128A CN 108047128 A CN108047128 A CN 108047128A CN 201711398046 A CN201711398046 A CN 201711398046A CN 108047128 A CN108047128 A CN 108047128A
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刘建明
岳园园
赵淑芳
闫旭洋
王智贤
王智玥
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Henan Normal University
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Abstract

本发明公开了一种合成(E)‑2‑甲基‑4‑苯基‑6‑苯乙烯基取代吡啶化合物的方法，属于有机化学技术领域。以(2E,3E)‑4‑苯基丁‑3‑烯‑2‑酮‑O‑乙酰肟类化合物为原料，在亚硫酸氢钠和溴化亚铜存在下，反应溶剂中加热反应得到(E)‑2‑甲基‑4‑苯基‑6‑苯乙烯基取代吡啶化合物。本发明利用两分子(2E,3E)‑4‑苯基丁‑3‑烯‑2‑酮‑O‑乙酰肟，一步反应即可构建功能性多取代吡啶类化合物，反应收率高，底物适用范围广泛。

Description

一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的 方法
技术领域
本发明属于有机合成技术领域，具体涉及一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法。
背景技术
吡啶作为一种重要的含氮杂环，存在于多种重要的化合物中，包括吖嗪、维生素烟酸、吡哆醇。它不仅是化学品和药物的前体，也是重要的助染剂和变性剂。吡啶衍生物是众多化合物的母体或片段结构，其构成了天然产物、功能材料、药物化学中的一类重要组成部分。正是由于其在各领域中的潜在应用前景，从而引起了科学家的重视与关注，并对此进行了大量研究，取得了众多有价值的科研成果。
吡啶衍生物的合成，尤其是取代的吡啶化合物，通常采用传统的交叉偶联反应，如金属催化的吡啶卤化物的反应，现有技术中已有诸多相关报道。传统的方法或工艺中均或多或少的存在诸多缺陷，例如：(1)采用昂贵的金属有机试剂、特殊的膦配体等，成本高昂，不利于工业化生产；(2)需要高温、多步反应，条件苛刻，限制了反应的实际应用；(3)产率、选择性仍不够高，有待进一步改进等等。因此，对于开发一种采用廉价催化剂、操作简便、成本低、收率高的取代吡啶衍生物的合成工艺，成为广大科研工作者的目标所在，其不但具有迫切的研究价值，也具有良好的经济效益和工业应用潜力。
发明内容
为了克服上述所指出的诸多缺陷，进而寻求合成取代吡啶化合物的简便方法，本发明公开了一种简单、有效、便捷合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法。从简单易得的试剂出发，经由简便的操作步骤，在温和的反应条件下，经过一步反应即可得到(E)-2-甲基-4-苯基-6-苯乙烯基取代的吡啶化合物的方法，避免了传统合成方法原料复杂、条件苛刻等弊端，成功合成了多官能化吡啶。
一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法，本发明采用的技术方案，其特征在于，包括以下操作：将(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、在铜催化剂和亚硫酸氢钠存在下，有机溶剂中加热反应得到(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物2。
其中：
Ar选自苯基、4-甲基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-叔丁基苯基、2,4-二甲基苯基、3,4-二甲基苯基、2,4,6-三甲基苯基、3-甲基苯基、3-甲氧基苯基，3-氟苯基、3-氯苯基、2-甲氧基苯基，2-氟苯基、2-氯苯基、联苯基、噻吩基、苯并噻吩基、呋喃基、苯并呋喃基。
进一步地，所述铜催化剂为溴化亚铜。所述加热反应时，温度控制在60-150℃，优选80-120℃。
进一步地，所述反应溶剂选自1,4-二氧六环、甲苯、氯苯、乙腈、THF、DMAC、DMF或NMP；进一步地，在使用1-4当量的亚硫酸氢钠做为还原剂时，反应能达到很好的促进效果。
进一步地，反应在惰性气体保护下进行，优选氮气保护。
进一步地，为了更好的理解本发明，以Ar＝苯基为底物进行条件优化为例：在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA(恒温磁力搅拌器)中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2,收率68％，改变其它反应条件时，结果如下：
在上述反应中，改变反应条件时，结果如下：
1)将溴化亚铜的量更换至0.015mmol和0.06mmol时，分离收率分别为39％和52％。
2)将亚硫酸氢钠的量更换至0.6mmol和1.2mmol时，分离收率分别为45％和57％。采用亚硫酸钠替换亚硫酸氢钠时，没有检测到反应产物。
3)采用氯化亚铜、碘化亚铜、溴化铜、醋酸铜、乙酰丙酮铜或溴化亚铜体系时，分离收率分别为45％、46％、52％、30％、47％、68％。
4)采用其它反应溶剂，如甲苯、氯苯、乙腈、1,4-二氧六环、THF、DMAC、DMF或NMP时，产率分别为45％、59％、43％、68％、54％、47％、55％、29％。
5)反应温度为80℃、90℃、120℃、130℃时，反应收率分别对应为40％，64％，41％和45％。
为了进一步理解反应机理，做了如下对比试验：
推测反应机理如下：
一分子反应物(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟化合物在铜催化剂的条件下，N-O键断裂形成氮自由基，含氮自由基前体进攻另一分子的不饱和键受体，然后通过还原消除，氧化加成得到目标产物。
发明有益效果：
1)本发明方法实验步骤少，技术难度低，条件温和，易于操作。本发明方法避免了使用多步反应的过程，反应一步即可完成。
2)本发明实现了一种反应物既可以做自由基前体，又可以做自由基受体，解决了含氮自由基进攻不饱和键的环加成选择性加成。
具体实施例：
通过以下实例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下实例，凡基于本发明上述内容实现的技术均属于本发明的范围。
本实施例1-9研究了多种苯环被吸电子基和供电子基取代，以及萘和杂环取代的(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟化合物自身偶联反应。
根据以上实验可以发现，该反应对苯环的烷基、甲氧基、氟代、氯代、溴代等取代基以及杂环均有广泛的底物适应性，得到了较高产率的对应目标产物。
代表性反应过程操作如下：
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟化合物1、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA(恒温磁力搅拌器)中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2a-2i。反应方程式如下：
续表
实施例1：(E)-2-甲基-4-苯基-6-苯乙烯基吡啶2a
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1a、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2a(68％)。该化合物的表征数据如下：1H NMR(600MHz,CDCl3)：7.65(dd,J＝12.0,6.0Hz,3H),7.60(d,J＝6.0Hz,2H),7.49(t,J＝9.0Hz,2H),7.43(t,J＝6.0Hz,2H),7.37(t,J＝6.0Hz,2H),7.29(t,J＝6.0Hz,1H),7.24(dd,J＝12.0,6.0Hz,2H),2.65(s,3H)；13C NMR(101MHz,CDCl3)：158.8,155.7,149.3,138.7,136.8,132.6,129.0,128.9,128.7,128.5,128.2,127.1,127.1,119.9,117.2,24.8；HRMS,calculated for C20H18N(M+H+):272.1434,found:272.1433.
实施例2：(E)-2-甲基-6-(4-甲基苯乙烯基)-4-对甲苯基吡啶2b
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1b、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2b(59％)。
实施例3：(E)-4-(4-甲氧基苯基)-2-(4-甲氧基苯乙烯基)-6-甲基吡啶2c
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1c、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2c(63％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.63-7.53(m,5H),7.39(s,1H),7.18-7.08(m,2H),7.02-7.00(m,2H),6.91(d,J＝8.0Hz,2H),3.87(s,3H),3.84(s,3H),2.63(s,3H)；13C NMR(151MHz,CDCl3)：160.4,159.8,158.5,155.9,148.7,132.1,131.0,130.5,129.6,128.4,128.2,128.0,126.4,119.0,116.4,114.4,114.3,114.2,113.7,55.4,55.3,24.7；HRMS,calculated for C22H22NO2(M+H+):332.1645,found:332.1643.
实施例4：(E)-2-甲基-4-(萘-2-基)-6-(2-(萘-2-基)乙烯基)吡啶2d
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1d、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2d(89％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：8.15(s,1H),7.98-7.94(m,3H),7.91-7.78(m,7H),7.62(s,1H),7.57-7.44(m,4H),7.42-7.38(m,2H),2.71(s,3H)；13C NMR(101MHz,CDCl3)：158.9,155.8,149.2,135.9,134.4,133.7,133.5,133.4,133.4,132.8,128.8,128.8,128.4,128.4,128.2,127.7,127.7,126.7,126.7,126.4,126.2,124.7,123.8,120.1,117.5,24.8；HRMS,calculated for C28H22N(M+H+):372.1747,found:372.1748.
实施例5：(E)-2-甲基-4-(噻吩-3-基)-6-(2-(噻吩-3-基)乙烯基)吡啶2e
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1e、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2e(56％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.66-7.62(m,2H),7.44-7.37(m,5H),7.33-7.31(m,1H),7.20(s,1H),7.04(d,J＝16.0Hz,1H),2.61(s,3H)；13C NMR(101MHz,CDCl3)：158.8,155.8,143.5,139.9,139.7,128.3,126.9,126.7,126.3,125.9,125.2,124.1,122.8,118.9,116.1,24.7；HRMS,calculated for C16H14NS2(M+H+):284.0562,found:284.0559.
实施例6：(E)-4-三甲苯基-2-甲基-6-(2,4,6-三甲基苯乙烯基)吡啶2f
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1f、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2f(52％)。
实施例7：(E)-4-(4-氟苯基)-2-(4-氟苯乙烯基)-6-甲基吡啶2g
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1g、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2g(78％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.62(td,J＝8.0,4.0Hz,3H),7.56(td,J＝6.0,4.0Hz,2H),7.36(d,J＝4.0Hz,1H),7.19-7.04(m,6H),2.64(s,3H)；13C NMR(151MHz,CDCl3)：163.3(JCF＝249Hz),162.7(JCF＝248Hz),158.9,155.6,148.3,134.7(JCF＝3.0Hz),132.9(JCF＝3.0Hz),131.6,128.8(JCF＝7.6Hz),128.7(JCF＝7.6Hz),128.0(JCF＝1.5Hz),119.7,117.1,116.0(JCF＝21.1Hz),115.7(JCF＝21.1Hz),24.8；HRMS,calculated for C20H16NF2(M+H+):308.1245,found:308.1252.
实施例8：(E)-4-(呋喃-2-基)-2-(2-(呋喃-2-基)乙烯基)-6-甲基吡啶2h
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1h、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2h(44％)。
实施例9：(E)-4-(苯并[b]噻吩-2-基)-2-(2-(苯并[b]噻吩-2-基)乙烯基)-6-甲基吡啶2i
在氮气气氛下，将0.6mmol(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟类化合物1i、0.9mmol亚硫酸氢钠、0.03mmol溴化亚铜和2mL 1,4-二氧六环依次加入到Schlenk反应管中，在IKA中恒温加热至100℃搅拌反应12h。反应结束后，冷却至室温，用20mL乙酸乙酯将反应液转移出来，减压旋蒸制样，经过柱层析分离得到目标产物2i(74％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3)：7.92(d,J＝16.0Hz,1H),7.87-7.85(m,1H),7.80(td,J＝8.0,4.0Hz,2H),7.75-7.71(m,2H),7.45(s,1H),7.39-7.37(m,3H),7.33-7.31(m,3H),7.07(d,J＝16.0Hz,1H),2.65(s,3H)；13C NMR(151MHz,CDCl3)：159.2,155.1,142.3,142.2,141.3,140.2,140.1,139.8,139.4,129.8,126.6,125.4,125.2,125.1,124.9,124.6,124.2,123.7,122.5,122.3,121.9,118.8,116.6,24.8；HRMS,calculated for C24H18NS2(M+H+):384.0875,found:384.0884.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (7)

1.一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法，其特征在于，包括以下操作：将(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、在铜催化剂和亚硫酸氢钠存在下，有机溶剂中加热反应得到(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物2，反应方程式如下：
2.根据权利要求1一种合成(E)-2-甲基-4-苯基-6-苯乙烯基取代吡啶化合物的方法，其特征在于：所述Ar选自苯基、4-甲基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-叔丁基苯基、1,4-二甲基苯基、3,4-二甲基苯基、2,4,6-三甲基苯基、3-甲基苯基、3-甲氧基苯基，3-氟苯基、3-氯苯基、2-甲氧基苯基，2-氟苯基、2-氯苯基、联苯基、噻吩基、苯并噻吩基、呋喃基或苯并呋喃基。
3.根据权利要求1或2所述的合成方法，其特征在于：所述铜催化剂选自氯化亚铜、溴化亚铜、碘化亚铜、溴化铜、醋酸铜、乙酰丙酮铜中的任意一种。
4.根据权利要求1所述的合成方法，其特征在于：所述有机溶剂为四氢呋喃、1,4-二氧六环、甲苯、氯苯、乙腈、DMF、NMP、DMSO、DMAC中的任何一种。
5.根据权利要求1所述的合成方法，其特征在于：所述(2E,3E)-4-苯基丁-3-烯-2-酮-O-乙酰肟1、铜催化剂与亚硫酸氢钠摩尔比为1：0.05-1：1-5。
6.根据权利要求1所述的合成方法：所述加热反应时，温度控制在60-150℃。
7.根据权利要求1所述的合成方法：所述反应在惰性气体保护下进行。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110117262A (zh) * 2019-04-30 2019-08-13 同济大学 2-苯乙烯基苯并恶唑或苯并噻唑基酮肟酯类化合物及其制备方法和应用
CN110407830A (zh) * 2019-08-21 2019-11-05 河南师范大学 一种合成n-芳基吩噻嗪类化合物的方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110117262A (zh) * 2019-04-30 2019-08-13 同济大学 2-苯乙烯基苯并恶唑或苯并噻唑基酮肟酯类化合物及其制备方法和应用
CN110117262B (zh) * 2019-04-30 2023-04-11 同济大学 2-苯乙烯基苯并恶唑或苯并噻唑基酮肟酯类化合物及其制备方法和应用
CN110407830A (zh) * 2019-08-21 2019-11-05 河南师范大学 一种合成n-芳基吩噻嗪类化合物的方法

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